Pharmacological actions of a novel NO‐independent guanylyl cyclase stimulator, BAY 41‐8543: in vitro studies

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Abstract
BAY 41‐8543 is a novel, highly specific and so far the most potent NO‐independent stimulator of sGC. Here we report the effects of BAY 41‐8543 on the isolated enzyme, endothelial cells, platelets, isolated vessels and Langendorff heart preparation. BAY 41‐8543 stimulates the recombinant sGC concentration‐dependently from 0.0001 μM to 100 μM up to 92‐fold. In combination, BAY 41‐8543 and NO have synergistic effects over a wide range of concentrations. Similar results are shown in implying that BAY 41‐8543 stimulates the sGC directly and furthermore makes the enzyme more sensitive to its endogenous activator NO. In vitro, BAY 41‐8543 is a potent relaxing agent of aortas, saphenous arteries, coronary arteries and veins with IC50‐values in the nM range. In the rat heart Langendorff preparation, BAY 41‐8543 potently reduces coronary perfusion pressure from 10−9 to 10−6 g ml−1 without any effect on left ventricular pressure and heart rate. BAY 41‐8543 is effective even under nitrate tolerance conditions proved by the same vasorelaxing effect on aortic rings taken either from normal or nitrate‐tolerant rats. BAY 41‐8543 is a potent inhibitor of collagen‐mediated aggregation in washed human platelets (IC50=0.09 μM). In plasma, BAY 41‐8543 inhibits collagen‐mediated aggregation better than ADP‐induced aggregation, but has no effect on the thrombin pathway. BAY 41‐8543 is also a potent direct stimulator of the cyclic GMP/PKG/VASP pathway in platelets and synergizes with NO over a wide range of concentrations. These results suggest that BAY 41‐8543 is on the one hand an invaluable tool for studying sGC signaling in vitro and on the other hand its unique profile may offer a novel approach for treating cardiovascular diseases. British Journal of Pharmacology (2002) 135, 333–343; doi:10.1038/sj.bjp.0704484